The synthesis of all opiate-derived analgesic agents as well as the various antagonists or mixed agonists currently used in medicine originates in naturally occurring alkaloids isolated from the opium poppy latex. The most commonly used are morphine and its congeners codeine, thebaine, and oripavine, shown in Scheme 1.

There are two major challenges in the large scale manufacture of the ubiquitously used pharmaceutical agents such as oxycodone, oxymorphone, naltrexone, naloxone, and nalbuphone, also shown in Scheme 1.
The first of the two challenges, the introduction of the C-14 hydroxyl represents an important step in the manufacture of all of these compounds. Nevertheless, this problem has been adequately solved by various oxidation protocols and thebaine and oripavine lend themselves as especially convenient starting materials for the C-14 hydroxylated analogs. Thus one would not expect that much improvement could be incorporated into the manufacturing process save for completely new methods involving C—H activation or biological catalysis. The second challenge, and a much more difficult one, rests in the formal exchange of the N-methyl group of natural opiates for the N-cyclopropylmethyl, N-allyl, or N-cyclobutylmethyl functionality found in naltrexone, naloxone, and nalbuphone, respectively.
The N-demethylation protocols previously reported include the von Braun reaction employing cyanogen bromidei, chloroformate reagentsii, photochemical methodsiii, demethylation of N-oxidesiv, as well as microbialv and enzymaticvi methods. The secondary amines are then converted to the corresponding products by alkylation. N-Demethylation/acylation of hydrocodone and tropane alkaloids was also accomplished via palladium catalysts that provided N-acetylhydrocodone and other acyl derivatives.vii 